DIX domains of Dvl and axin are necessary for protein interactions and their ability to regulate beta-catenin stability

Department of Biochemistry, Hiroshima University School of Medicine, Minami-ku, Hiroshima 734-8551, Japan.
Molecular and Cellular Biology (Impact Factor: 4.78). 07/1999; 19(6):4414-22. DOI: 10.1128/MCB.19.6.4414
Source: PubMed


The N-terminal region of Dvl-1 (a mammalian Dishevelled homolog) shares 37% identity with the C-terminal region of Axin, and
this related region is named the DIX domain. The functions of the DIX domains of Dvl-1 and Axin were investigated. By yeast
two-hybrid screening, the DIX domain of Dvl-1 was found to interact with Dvl-3, a second mammalian Dishevelled relative. The
DIX domains of Dvl-1 and Dvl-3 directly bound one another. Furthermore, Dvl-1 formed a homo-oligomer. Axin also formed a homo-oligomer,
and its DIX domain was necessary. The N-terminal region of Dvl-1, including its DIX domain, bound to Axin directly. Dvl-1
inhibited Axin-promoted glycogen synthase kinase 3β-dependent phosphorylation of β-catenin, and the DIX domain of Dvl-1 was
required for this inhibitory activity. Expression of Dvl-1 in L cells induced the nuclear accumulation of β-catenin, and deletion
of the DIX domain abolished this activity. Although expression of Axin in SW480 cells caused the degradation of β-catenin
and reduced the cell growth rate, expression of an Axin mutant that lacks the DIX domain did not affect the level of β-catenin
or the growth rate. These results indicate that the DIX domains of Dvl-1 and Axin are important for protein-protein interactions
and that they are necessary for the ability of Dvl-1 and Axin to regulate the stability of β-catenin.

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    • "Further investigation identified that the DIX and PDZ domain of Dvl was required for Lrp6 phosphorylation. PDZ interacts with Frz, whereas DIX interacts with Axin (Kishida et al., 1999; Wong et al., 2003; Zeng et al., 2008). This suggests a sequence of events: Wnt ligand interacts with Frz and Lrp6, then Frz recruits Dvl to the membrane, which in turn, recruits Axin and its associated proteins such as GSK3β to the Wnt signaling complex or Wnt signalosome. "
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    ABSTRACT: Nkd1 is a negative feedback inhibitor of Wnt signaling known to antagonize Wnt signaling in the cytoplasm by inhibiting the nuclear accumulation of the central signaling component β-catenin. In this thesis, I test the hypothesis that Nkd1 needs to be activated by a Wnt ligand in order for proper function. By stimulating Wnt signaling by a Wnt ligand or a constitutively active receptor, I found that only in the presence of a Wnt ligand does the cellular distribution of Nkd1 change from large punctae to smaller punctae distributed throughout the cytoplasm. Moreover, only in the presence of a Wnt ligand does Nkd1 have the ability to antagonize Wnt signaling and block the nuclear accumulation of β-catenin. Taken together, my data suggests that Nkd1 function and localization are critically dependent on the presence of a Wnt ligand.
    Full-text · Thesis · Jan 2014
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    • "The interaction of Dsh with Fz is known to be important for planar-cell polarity (reviewed in Seifert and Mlodzik, 2007), a non-canonical Wnt signaling process. Since Dsh also binds to Axin (Kishida et al., 1999; Smalley et al., 1999), Dsh-Fz interaction may facilitate recruitment of Axin to the Arrow/LRP cytosolic domain. This Axin movement could be a crucial event in pathway activation (Cliffe et al., 2003; Lee et al., 2003). "
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    ABSTRACT: Wnt signaling generates pattern in all embryos, from flies and worms to humans, and promotes the undifferentiated, proliferative state critical for stem cells in adult tissues. Inappropriate Wnt pathway activation is the major cause of colorectal cancers, a leading cause of cancer death in humans. Although this pathway has been studied extensively for years, large gaps remain in our understanding of how it switches on and off, and how its activation changes cellular behaviors. Much of what is known about the pathway comes from genetic studies in Drosophila, where a single Wnt molecule, encoded by wingless (wg), directs an array of cell-fate decisions similar to those made by the combined activities of all 19 Wnt family members in vertebrates. Although Wg specifies fate in many tissues, including the brain, limbs and major organs, the fly embryonic epidermis has proven to be a very powerful system for dissecting pathway activity. It is a simple, accessible tissue, with a pattern that is highly sensitive to small changes in Wg pathway activity. This review discusses what we have learned about Wnt signaling from studying mutations that disrupt epidermal pattern in the fly embryo, highlights recent advances and controversies in the field, and sets these issues in the context of questions that remain about how this essential signaling pathway functions. Mol. Reprod. Dev. © 2013 Wiley Periodicals, Inc.
    Preview · Article · Nov 2013 · Molecular Reproduction and Development
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    • "This structure might contribute to make open interphase to bind to other proteins that are involved in abscission. As previously reported, Dvl oligomerizes via its DIX domain (Kishida et al., 1999; Schwarz-Romond et al., 2007), and therefore it is intriguing to speculate that oligomerization might be required for the structure formation and efficient stabilization of midbody microtubules. SIM image also revealed that Fz2 forms discontinuous ring structures at late telophase. "
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    ABSTRACT: Wnts activate at least two signaling pathways, the β-catenin-dependent and -independent pathways. Although the β-catenin-dependent pathway is known to contribute to G1/S transition, involvement of the β-catenin-independent pathway in cell cycle regulation remains unclear. Here, we show that Wnt5a signaling, which activates the β-catenin-independent pathway, is required for cytokinesis. Dishevelled 2 (Dvl2), a mediator of Wnt signaling pathways, was localized to the midbody during cytokinesis. Beside the localization of Dvl2, Fz2, a Wnt receptor, was detected in the midbody with an endosomal sorting complex required for transport III (ESCRT-III) subunit, CHMP4B. Depletion of Wnt5a, its receptors, and Dvl increased multinucleated cells. The phenotype observed in Wnt5a-depleted cells was rescued by the addition of purified Wnt5a but not that of Wnt3a, which is a ligand for the β-catenin-dependent pathway. Moreover, depletion of Wnt5a signaling caused loss of stabilized microtubules and mislocalization of CHMP4B in the midbody, which affected abscission. Inhibition of the stabilization of microtubules at the midbody lead to the mislocalization of CHMP4B, while depletion of CHMP4B did not affect the stabilization of microtubules, suggesting that the correct localization of CHMP4B depends on microtubules. Fz2 was localized to the midbody in a Rab11-dependent manner probably along stabilized microtubules. Fz2 formed a complex with CHMP4B upon Wnt5a stimulation and was required for proper localization of CHMP4B at the midbody, while CHMP4B was not necessary for the localization of Fz2. These results suggest that Wnt5a signaling positions ESCRT-III in the midbody properly for abscission by stabilizing midbody microtubules.
    Full-text · Article · Jul 2012 · Journal of Cell Science
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